Humans with idiopathic hypercalciuria (IH), the most common metabolic abnormality associated with human nephrolithiasis, and genetic hypercalciuric stone-forming (GHS) rats share a common physiology: high urine (U) calcium (Ca) excretion, high intestinal Ca absorption, reduced renal Ca reabsorption and, with low Ca diet (LCD), loss of bone mineral. Both have excessive vitamin D receptor (VDR) abundance. Administration of 1,25(OH)2D3 (1,25D3) to normal (nl) humans or rats leads to physiology that mimics IH and the GHS rat. In the 1st aim we will test the hypothesis that the hypercalciuria in GHS rats results from an inherited increase in VDR abundance so that 1,25D3 response is elevated, given nl 1,25D3 levels, leading to a form of endogenous 1,25D3 excess. If true, then vitamin D deficiency of graded severity should bring responses of the GHS rat into the nl range with respect to UCa, intestinal Ca absorption, and bone mineral balance. In vitamin D deficient GHS and Sprague-Dawley (SD) rats repleted with graded amounts of 1,25D3 below and above the physiological range, we will measure UCa, intestinal Ca absorption and VDR on a nl Ca diet. In parallel studies GHS and SD rats will be fed LCD to virtually eliminate absorbed Ca and UCa and VDR will be measured. In other similarly treated GHS and SD rats both fed LCD and given alendronate to virtually eliminate absorbed Ca and block bone resorption we will measure UCa and VDR. In all cases, at the lowest 1,25D3 repletion ranges, UCa from GHS and SD rats should be indistinguishable. GHS rats reabsorb renal tubular Ca less well than SD at fixed and equal PTH, Ca levels, and filtered loads of Ca. Renal cortical Ca sensing receptor (CaR) abundance is elevated in GHS rats, and its stimulation reduces Ca reabsorption in nl rats. 1,25D3, through VDR, can increase CaR. In the 2nd aim we will test the hypothesis that the high VDR of GHS rats leads to high renal CaR abundance resulting in reduced Ca reabsorption at nl blood Ca2+. If true, in the absence of PTH increasing blood Ca2+ should lower renal Ca reabsorption to a greater extent in GHS than in SD rats. Moreover, D depletion should reduce the difference of renal Ca reabsorption between GHS and SD rats to an indistinguishable level. In vitamin D replete, parathyroidectomized GHS and SD rats, we will vary blood Ca2+ from below to above the physiological range and calculate Ca fractional reabsorption during an acute clearance study and measure CaR and VDR. If CaR is a primary mechanism for reduced Ca reabsorption in GHS rats, then reabsorption should fall more in GHS than in SD. We will repeat the protocol in D depleted GHS and SD rats with varying degrees of 1,25D3 repletion. If VDR-driven excess of renal CaR is a main regulator, then at the lowest levels of 1,25D3 repletion the response of renal Ca reabsorption to blood Ca2+ of GHS and SD should be indistinguishable. These studies will advance IH research and may ultimately lead to improved care of patients with urolithiasis.Excess urine calcium excretion, hypercalciuria, is the most common metabolic abnormality associated with kidney stones in humans. We have developed an animal model of hypercalciuria and propose to use these rats to determine if increases in receptors for vitamin D and/or for calcium are responsible, at least in part, for the hypercalciuria. These studies will advance research on hypercalciuria and may ultimately lead to improved care of patients with kidney stones.